Objective

"Despite years of promise, an odor-emitting component in devices such as televisions, phones, computers and more has yet to be developed. Two major obstacles in the way of such development are poor understanding of the olfactory code (the link between odorant structure, neural activity, and odor perception), and technical inability to emit odors in a reversible manner. Here we propose a novel multidisciplinary path to solving this basic scientific question (the code), and in doing so generate a solution to the technical limitation (controlled odor emission). The Bachelet lab will design DNA strands that assume a 3D structure that will specifically bind to a single type of olfactory receptor and induce signal transduction. These DNA-based ""artificial odorants"" will be tagged with a nanoparticle that changes their conformation in response to an external electromagnetic field. Thus, we will have in hand an artificial odorant that is remotely switchable. The Hansson lab will use tissue culture cells expressing insect olfactory receptors, functional imaging, and behavioral tests to validate the function and selectivity of these switchable odorants in insects. The Carleton lab will use imaging in order to investigate the patterns of neural activity induced by these artificial odorants in rodents. The Sobel lab will apply these artificial odorants to the human olfactory system, and measure perception and neural activity following switching the artificial smell on and off. Finally, given a potential role for olfactory receptors in skin, the Del Rio lab will test the efficacy of these artificial odorants in promoting wound healing. At the basic science level, this approach may allow solving the combinatorial code of olfaction. At the technology level, beyond novel pharmacology, we will provide proof-of-concept for countless novel applications ranging from insect pest-control to odor-controlled environments and odor-emitting devices such as televisions, phones, and computers."

Nanosmell is a project where we aim to use nanotechnology, or more specifically developments of a method known as DNA origami, in order to shape strands of DNA into ligands for specific olfactory receptors. We call these intended designer odorants NanoSmells. Moreover, we aim to design a remote switch into NanoSmells such that we will be able to turn these odors “on” and “off” remotely. In the project, the Bachelet lab (Augmanity, Israel) will use nanotechnology to design and generate NanoSmells, the Hansson lab (Max Plank, Germany) will test the response to NanoSmells in the insect brain and behavior, the Carleton lab (University of Geneva, Switzerland) will test the response to NanoSmells in the rodent brain and behavior, the Del-Rio lab (University of Madrid, Spain) will test the effectiveness of NanoSmells as agents of healing skin wounds, something natural odorants may do. Finally, the Sobel lab (Weizmann Institute, Israel), the coordinating lab, will test the response to NanoSmells in human brain and behavior. If successful, on the basic science side this high-risk high-gain project may provide definitive insight into how the brain codes odors, and on the technology side this project may pave the way for odor into media, including controlled odor-emitting phones, televisions, computers and beyond.

After one year of efforts we report the following progress: This project has a clearly acknowledged rate-limiting risk factor and that is the initial development of NanoSmells at the Bachelet lab for the other labs to work with. While the Bachelet lab was busy with this during the first year, the other labs put in place the setups needed to then test NanoSmells. This included a dedicated setup at the Hansson lab to allow application of non-volatile compounds to the insect antenna, a dedicated setup at the Carleton lab to test brain responses to the project target odor, a dedicated setup at the Del-Rio lab to apply odorants to skin, and a dedicated setup at the Sobel lab to test the notion of human olfactory perception without “odor”. More specifically, before using NanoSmells, the Sobel lab investigated whether they could use electrical currents applied in the human nose to generate a sense of smell. They found that nasal currents failed to generate a sense of odor, but did activate the brain’s olfactory system. This has serendipitously pointed to a potential novel path to human brain stimulation, an important aspect of treatment in several brain diseases. This result has culminated in the first NanoSmell publication (Weiss et al., Cerebral Cortex 2016). As to the generation of NanoSmells at the Bachelet lab, the bad news is that this has taken longer than expected, but the good news is that this is finally under way. The Bachelet lab has recently made significant progress and groundbreaking developments in nanotechnology to generate NanoSmells. This has allowed them to first ship a version of provisional NanoSmells to all participating groups. We refer to these as provisional because they did not go through all the intended phases of NanoSmell selection. Currently, the Bachelet lab is finally entering the final stages of complete NanoSmell generation. As to results with the provisional NanoSmells, the Hansson group failed to observe a response in insects, the Carleton lab observed inconclusive responses in rodents, the Del-Rio lab is awaiting final outcome in skin, and the Sobel lab failed to observe responses in humans. This final set of extensive tests in the Sobel lab is rather definitive in concluding that the provisional NanoSmells do not have a smell. Although disappointing, we are far from being discouraged, as the path to NanoSmells was clearly going to be a long path, and this was but the first pass. We are hopeful and more confident as to the second generation of NanoSmells to soon be sent from the Bachelet lab to the participating groups.

First, we have developed new methods for selecting aptamers that bind to trans-membrane receptors (GPCRs). In addition to advancing us towards the goal of our project, these methods may serve in identifying ligands to treat various disease states related to specific receptors.

Second, we have generated a novel method for human deep brain stimulation. This may provide a novel path to treatment of conditions such as intractable epilepsy and depression.

Rodent bulb maps at Month 47. This deliverable is the responsibility of UNIVERSITE DE GENEVE. Here they will generate bulb activation maps following activation of a single receptor. This should provide important insight on the coding rules of olfaction.

Final human response at Month 24. This deliverable is the responsibility of WEIZMANN. We expect a final manuscript co-authored by WEIZMANN and BIU describing the perceptual and neural response of humans to artificial odorants.

Final skin response at Month 24. This deliverable is the responsibility of UC3M. We expect a final manuscript co-authored by UC3M and AN describing the response of skin wounds to the artificial odorant.

Switchable wound treatment at Month 47. This deliverable is the responsibility of UC3M. Here we will test the response of wounds to remote activation in vivo. If this works, one can imagine a product worn by people at high risk of injury, e.g., fire fighters, and if they get injured, then the treatment can be remotely activated.

Human rapidly switchable odors at Month 47. This deliverable is the responsibility of WEIZMANN. Here we will remotely activate an odor at percise timing with media, such as at an appropriate time in a film.